The proposed studies aims to elucidate the dynamics of red blood cell (RBC) sequestration in capillaries of patients with sickle cell disease (SCD). The basic approach is to use the non-invasive technique of nailfold microscopy to observe the transit of RBCs through skin capillaries at the base of the fingernail. Video recordings will be made of capillaries in patients with SCD during periods of steady state (crisis free) and vaso- occlusive crisis. These recordings will be digitized and analyzed to obtain red blood cell velocity (V RBC) in the resting state during the provocation test of post-occlusive reaction hyperemia (PORH). The PORH will be induced by cessation of blood flow for period of one minute by inflation of a pressure cuff around the proximal digit. During the onset of stasis induced by the occlusion, and during shorter periods of occlusion as well, the transient reductions in V RBC will be analyzed to obtain quantitative indices of accumulation of RBCs in the skin capillaries with the onset of stasis. Preliminary studies have served to formulate an accumulation index (AI) that represents the percentage of the RBC flux flowing into a capillary that becomes sequestered in the capillary; AI show shown to increase dramatically with reductions in shear rate (Y) below a transition value, YT and it was shown that for HbSS subjects, AI and Y T are significantly increased in steady state (compared to normal HbAA subjects) and increase further dealing crisis, presumable due to enhanced RBC to endothelium adhesion. Thus the proposed studies will seek correlates of these parameters with the occurrence and frequency of crisis in individual subjects, the size and deformability of RBCs of various hemoglobinopathies (e.g. HbSS alpha-thalassemia) and plasma levels of soluble adhesion molecule ICAM-1, VCAM-1 that have been shown to be correlated with enhanced RBC-endothelium adhesion. In addition, RBC dynamics in the nailfold will be correlated with systemic leukocyte count and circulating levels of the adhesion molecules I-CAM and V-CAM, L- selectin, P-selectin and E-selectin. Deformability of HbSS and other RBCs will be obtained for correlation with the studies of nailfold microscopy by examining their in vitro filterability through the 5mum diameter pores of Nuclepore filters. It is anticipated that the results of these studies will provide new and useful information to guide the clinical management of SCD.